Chronic pain is a complex and debilitating condition that profoundly affects an individual’s quality of life. In the United States, nearly a quarter of adults experienced some form of persistent pain in 2023, with women disproportionately affected compared to men. The underlying causes of chronic pain are diverse, ranging from nerve damage and joint degeneration to systemic inflammatory processes. Researchers point to immune-inflammatory crosstalk as a primary driver of persistent pain, wherein immune cells—such as macrophages and T lymphocytes—release inflammatory mediators that activate and sensitize peripheral nerves.
Recently, a team of scientists led by Xuming Zhang at the University of Warwick made a groundbreaking discovery in mice: an ion channel in sensory neurons traditionally known for detecting warmth also functions as a chronic pain sensor. Crucially, this pain-sensing mechanism operates independently of the immune-mediated inflammation typically associated with long-lasting pain. Published in the Proceedings of the National Academy of Sciences, these findings reveal a novel pathway through which neurons detect and transmit painful signals, offering a promising new target for the development of innovative pain therapies.
“We understand acute pain reasonably well, but chronic pain really remains very much a black box,” remarked Peter McNaughton, a neuroscientist at King’s College London who was not involved in the study but has collaborated with Zhang in the past. “This research represents a promising starting point, and I am confident that either this team or other researchers will build upon these findings to uncover further mechanisms over time.”
Ion Channels That Detect Warmth and Pain
For years, Zhang has dedicated his research to uncovering the cellular and molecular underpinnings of pain. Among the vast array of ion channels and receptors involved in detecting and transmitting painful signals, his work has focused on a specific family known as transient receptor potential (TRP) channels. First identified in the late 1960s, these molecular sensors are widely expressed across various organs and cell types, including both immune cells and nerve cells.
In his lab at University of Warwick, researcher Xuming Zhang (center) and his team study the cellular and molecular mechanisms of pain.
Yuru Zhi
A decade ago, McNaughton’s team identified a specific subset of the TRP family called transient receptor potential melastatin 2 (TRPM2) within sensory neurons, which are responsible for detecting non-painful warm temperatures. While a significant portion of sensory neurons express TRPM2, McNaughton noted that less than five percent of them are actually involved in warmth detection. This observation led to a pivotal question: “The question that Xuming Zhang’s group has picked up on is what are the rest of [these neurons] doing,” he explained.
Zhang explained that TRPM2-expressing immune cells are known to amplify immune and inflammatory responses, thereby contributing to pain. Given this evidence, alongside the presence of these ion channels in sensory neurons, Zhang and his team hypothesized that the non-warmth-related TRPM2 channels in sensory neurons might also mediate persistent pain. To investigate this, the researchers utilized two distinct mouse models of chronic pain: one simulating neuropathic pain caused by nerve damage, and another modeling inflammation-mediated pain similar to that seen in rheumatoid arthritis.
The study revealed a significant reduction in pain among animals that either lacked the TRPM2 ion channel or had their channel activity blocked by a drug. To isolate the effects from immune cell-mediated TRPM2 actions, the team conducted pain assessments on animals selectively lacking the ion channels only in sensory neurons. These animals exhibited pain mitigation comparable to that of whole-body TRPM2 knockout mice, highlighting the critical role of neuronal TRPM2 channels in both neuropathic and arthritic pain.
“The prevailing thought was that this channel functioned predominantly within the immune system. Based on this paper, it appears that many of those assumptions were actually the inverse,” noted Candice Paulsen, a biochemist at Yale University who was not involved in the study. “The meticulous detective work involved in selectively knocking out the channel allowed the researchers to truly clarify its specific role, which was incredibly exciting.”
TRPM2: A Potential Chronic Pain Drug Target
To pinpoint the cellular mechanisms underlying TRPM2-mediated pain, the researchers examined key molecules associated with chronic pain. They discovered that Prostaglandin E2 (PGE2) and Immunoglobulin G immune complexes (IgG-IC) activate TRPM2 channels through distinct pathways, ultimately enhancing the excitability of sensory neurons.
Although neuronal TRPM2 detects harmful stimuli in these chronic pain models, the researchers found that it primarily functions during the early stages of persistent pain development. Mice lacking the channel eventually regained the ability to sense pain over time, indicating a time-sensitive role. “I hadn’t really considered the specific timeframe during which a pain receptor might play a more dominant or minor role; that aspect was particularly striking to me,” remarked Paulsen.
Looking forward, TRPM2 presents itself as an attractive therapeutic target. However, for an effective pain-mitigation strategy to be developed, Paulsen suggests that other molecules alongside TRPM2 should be targeted, given that its effects are confined to a limited time window. “This discovery is exciting because it identifies one of these key molecules, revealing that there are many more components to investigate as we work to understand how they integrate into larger pain pathways,” she concluded.
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